Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the present invention is related to O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides which are useful in a mammalian host for the treatment of autoimmune diseases (such as juvenile-onset or recent-onset diabetes mellitus, multiple sclerosis, rheumatoid arthritis, liver disease, posterior uveitis, allergic encephalomyelitis, and glomerulonephritis, infectious diseases and/or the prevention of rejection of foreign organ transplants, e.g.
• autoimmune diseases such as juvenile-onset or recent-onset diabetes mellitus, multiple sclerosis, rheumatoid arthritis, liver disease, posterior uveitis, allergic encephalomyelitis, and glomerulonephritis
• infectious diseases such as juvenile-onset or recent-onset diabetes mellitus, multiple sclerosis, rheumatoid arthritis, liver disease, posterior uveitis, allergic encephalomyelitis, and glomerulonep
• inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses such as: psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus or Alopecia areata), reversible obstructive airways disease, particularly asthma, alopecia, inflammation of mucosa and blood vessels, cytomegalovirus infection, multidrug resistance, idiopathic thrombocytopenic purpura, and/or hepatic
• immunologically-mediated illnesses such as: psoriasis, atopical dermatitis, contact dermatitis and
• this invention relates to compounds of the general structural Formula I: ##STR2## wherein R 1 , R 2 , R 3 , R 4 , R 5 , W and n are hereinafter defined.
• This invention also relates to pharmaceutical compositions containing the compounds, and to a method of use of the present compounds and other agents for the treatment and prevention of certain afflictions, diseases and illnesses.
• Antibiotics 1987, 40, 1249 disclose 17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 4 ,9 ]octacos-18-ene-2,3,10,16-tetraone (FR-900506) (FK-506) (L-679,934), 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0 4 ,9 ]-octacos-18-ene-2,3,10,16-tetraone
• 0,437,680 discloses chloro, bromo, iodo and azido derivatives of FR-900506, FR-900520 and related compounds.
• a Merck European patent application (EPO Publication No. 0,428,365) discloses various amino derivatives of FR-900506, FR-900520 and related compounds.
• a Fujisawa UK patent application (UK Publication No. GB 2,245,891A) discloses various aryl(lower alkyl) and heteroaryl derivatives of FR-900506, FR-900520 and related compounds.
• Fujisawa United States patents U.S. Pat. No. 4,929,611, issued May 29, 1990 and U.S. Pat. No. 4,956,352, issued Sep. 11, 1990 disclose the use of FK-506-type compounds in treating resistance to transplantation.
• a Sandoz European patent application (EPO Publication No. 0,315,978) discloses the use of FR-900506 and related compounds in the topical treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated illness.
• a Fisons World patent application (PCT Publication WO 90/14826) discloses the use of FR-900506 and related compounds in the treatment of reversible obstructive airways disease, particularly asthma.
• a Fujisawa European patent application discloses the use of FK-506 and derivatives as hair revitalizing agents.
• Various studies have suggested the efficacy of FK-506 in the treatment of a number of ailments, including rheumatoid arthritis (C. Arita, et al., Clinical exp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336, 373-74), posterior uveitis (H.
• Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Chron's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy.
• autoimmune systemic lupus erythematosis
• chronic rheumatoid arthritis type 1 diabetes mellitus
• inflammatory bowel disease e.g., chronic rheumatoid arthritis
• inflammatory bowel disease e.g., chronic rheumatoid arthritis
• biliary cirrhosis uveitis
• multiple sclerosis and other disorders such as
• the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
• autoimmune or a rejection process tissue destruction caused by inflammatory cells and the mediators they release.
• Antiinflammatory agents such as NSAID's and corticosteroids act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease.
• cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
• Cyclosporin A which was approved by the U.S. FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Though cyclosporin A is effective in fighting transplant rejection, it is nephrotoxic and is known to cause several undesirable side effects including kidney failure, abnormal liver function and gastrointestinal discomfort.
• the compound FK-506 and related compounds further have been suggested to be useful in the treatment of obstructive airways disease, particularly asthma (PCT Publication WO 90/14826), rheumatoid arthitis (C. Arita, et al., Clinical exp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, et al., Diabetes, 39, 1584-86; N. Murase, et al. Lancet, 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol. Vis.
• novel compound of this invention has structural Formula I: ##STR4## or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently selected from:
• R 6 and R 7 and the N to which they are attached can form an unsubstituted or substituted 3-7-membered saturated heterocyclic ring which can include one or two additional heteroatoms independently selected from the group consisting of O, S(O) p , NR 14 , wherein R 14 is hydrogen or C 1-6 alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,
• R 1 and R 2 are not simultaneously hydrogen, methyl or combinations thereof;
• R 3 is hydrogen, hydroxy, --OR 11 or C 1-6 alkoxy
• R 4 is hydrogen, or R 3 and R 4 taken together form a double bond
• R 5 is methyl, ethyl, propyl or allyl
• R 11 is selected from:
• W is O or (H, OH);
• X, Y and Z independently are selected from:
• R 9 O(CH 2 ) m -- wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,
• any two of adjacent X, y and Z can be joined to form a ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and
• n 1 or 2.
• the compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
• variable e.g., alkyl, aryl, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• alkyl includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration.
• alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
• Alkoxyl represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy.
• alkanoyl is intended to include those alkylcarbonyl groups of specified number of carbon atoms, which are exemplified by formyl, acetyl, propanoyl and butyryl;
• alkanoyloxy is intended to include those alkylcarbonyl groups of specified number of carbon atoms attached through an oxygen bridge, which are exemplified by formyloxy, acetoxy, propionoyloxy, and butyryloxy.
• Alkenyl is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched -configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Z forms, where applicable; and "arylalkyl” represents aryl groups as herein defined which are attached through a straight or branched chain alkyl group of from one to six carbon atoms, such as, for example, benzyl, phenethyl, 3,3-diphenylpropyl, and the like.
• Halogen as used herein, means fluoro, chloro, bromo and iodo.
• pharmaceutically acceptable salts include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or slats with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate.
• pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with amines of the formula HNR 6 R 7 ).
• R 1 and R 2 are independently selected from:
• R 1 and R 2 are not simultaneously hydrogen, methyl or combinations thereof;
• R 3 is hydrogen, hydroxy, or C 1-6 alkoxy
• R 4 is hydrogen, or R 3 and R 4 taken together form a double bond
• R 5 is methyl, ethyl, propyl or allyl
• R 11 is selected from:
• W is O or (H, OH);
• X, Y and Z are independently, selected from:
• R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,
• any two of adjacent X, Y and Z can be joined to form a ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and
• n 1 or 2.
• R 1 and R 2 are independently selected from:
• R 6 and R 7 and the N to which they are attached can form an unsubstituted or substituted 3-7-membered saturated heterocyclic ring which can include one or two additional heteroatoms independently selected from the group consisting of O, S(O) p , NR 14 , wherein R 14 is hydrogen or C 1-6 alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,
• R 1 and R 2 are not simultaneously hydrogen, methyl or combinations thereof;
• R 3 is hydrogen, hydroxy, --OR 11 or C 1-6 alkoxy
• R 4 is hydrogen, or R 3 and R 4 taken together form a double bond
• R 5 is methyl, ethyl, propyl or allyl
• R 11 is selected from:
• W is O or (H, OH);
• X, Y and Z independently are selected from:
• R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,
• any two of adjacent X, Y and Z can be joined to form a ring having 5, 6 or 7 atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and
• n 1 or 2.
• R 1 and R 2 are independently selected from:
• R 6 and R 7 and the N to which they are attached may form an unsubstituted or substituted 3-7-membered saturated heterocyclic ring which may
• R 14 is hydrogen or C 1-6 alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2, the ring being selected from the group consisting of: aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,
• R 1 and R 2 are not simultaneosuly hydrogen, methyl or combinations thereof;
• R 3 is hydrogen, or hydroxy
• R 4 is hydrogen
• R 5 is ethyl, propyl or allyl
• R 11 is selected from:
• W is O or (H, OH);
• X. Y and Z independently are selected from:
• R 9 O(CH 2 ) m - wherein R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,
• any two of adjacent X, Y and Z may be joined to form a ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, selected from the group consisting of: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dixoanyl; and
• n 2;
• Representative compounds of the present invention include the compounds identified as follows:
• W is O or (H, OH);
• R 3 is hydrogen, hydroxy, or C 1 -C 6 alkoxy
• R 4 is hydrogen, or R 3 and R 4 taken together form a double bond
• R 5 is methyl, ethyl, propyl or allyl
• n 1 or 2.
• Organisms belonging to the genus Streptomyces such as Streptomyces tsukubaensis, No. 9993 and Streptomyces hygroscopicus, No. 7238 placed in an aqueous nutrient medium will produce desired compounds in isolable amounts.
• the nutrient medium contains sources of assimilable carbon and nitrogen, preferably under aerobic conditions.
• Produced in fermentation are four compounds of Formula II, (A) where Q is methyl, W is O, R 3 is hydroxyl, R 4 is hydrogen, R 5 is allyl and n is 2; (B) where Q is methyl, W is O, R 3 is hydroxyl, R 4 is hydrogen, R 5 is ethyl and n is 2; (C) where Q is methyl, W is O, R 3 is hydroxyl, R 4 is hydrogen, R 5 is methyl and n is 2; and (D) where Q is methyl W is O, R 3 is hydroxyl, R 4 is hydrogen, R 5 is allyl and n is 1.
• the allyl of R 5 may be conveniently reduced to propyl by well known methods, for example as described in U.S. Pat. No. 4,894,366.
• the hydroxy of R 3 may be protected by well known methods, for example as disclosed in EPO Publication No. 0,323,042.
• the hydroxy at C-4" may also be protected.
• the hydroxy of R 3 may be reduced to a hydrogen or eliminated to form a double bond with R 4 (by methods disclosed in U.S. Pat. No. 4,894,366 or EPO Publication No. 0,323,042 or EPO Publication No. 0,413,532).
• the carbonyl of W may be reduced to the alcohol by methods disclosed in EPO Publication No. 0,323,042 or by methods disclosed in U.S. Pat. No. 5,064,835 or in EPO Publication No. 0,445,975.
• the methyl of Q as produced may be replaced with hydrogen or demethylated and subsequently protected as desired, if necessary.
• This demethylation of compounds wherein Q is methyl may be carried out in a fermentation reaction using the compounds of Formula II as a feedstock.
• compound A named under Formula II above may be demethylated at Q above by using the microorganism Actinomycetales ATCC No. 53771 (described in U.S. Pat. No. 4,981,792, issued Jan. 1, 1991) or by using the microorganism Streptomyces tsukubaensis, No. 9993 (described in EPO Publication No. 0,353,678).
• compound B named under Formula II above may be demethylated at Q above using the microorganism Actinoplanacete sp. ATCC No. 53771 (described in EPO Publication No. 0,349,061).
• the compound of Formula II wherein Q is H, W is O, R 3 is hydroxy, R 4 is hydrogen, R 5 is ethyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant of Streptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as described in EPO Publication 0,388,152).
• the compound of Formula II wherein Q is hydrogen, W is O, R 3 is hydroxy, R 4 is hydrogen, R 5 is methyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant of Streptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as described in EPO Publication 0,388,153).
• the compound of Formula II wherein Q is hydrogen, R 3 is hydroxy, R 4 is hydrogen, R 5 is allyl, W is 0 and n is 2 and the compound of Formula II wherein the C-3" position is oxo (keto), R 3 is hydroxy, R 4 is hydrogen, R 5 is allyl, W is O and n is 2 may be produced directly by fermentation using the microorganism Streptomyces tsukubaensis, No. 9993 (described in EPO Publication No. 0,353,678).
• the hydroxy of C-3" may be protected by methods similar to those known for the protection of the hydroxyl groups of R 3 and/or C-4", for example as disclosed in U.S. Pat. No. 4,894,366.
• Suitable protecting groups for hydroxyl include those groups well known in the art such as:
• lower alkylthio indicates a straight, cyclic or branched chain of one to six carbon atoms, such as lower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), and the like, in which the preferred one may be C 1 -C 4 alkylthiomethyl and the most preferred one may be methylthiomethyl; trisubstituted silyl such as tri(lower)alkylsilyl (e.g.
• a solution of a 4"-hydroxy-3"-methoxy macrolide in an inert organic solvent such as methylene chloride, benzene, toluene, chloroform, or the like or mixtures thereof is treated with a triarylbismuth diacetate reagent (wherein R 1 is aryl) (prepared immediately prior to use by the addition of acetic acid to a suspension of a triarylbismuth carbonate in an inert organic solvent such as methylene chloride, chloroform or the like or mixture thereof) in the presence of a catalytic amount of copper(II) acetate at a temperature of 20°-50° C., preferably room temperature, for a period of one hour to seven days, preferably one day, to give the 4"-O-aryl-3"-methoxy macrolide.
• an inert organic solvent such as methylene chloride, benzene, toluene, chloroform, or the like or mixtures thereof
• the triarylbismuth(V) reagent can be prepared by treatment of a triarylbismuthine with a suitable oxidant such as peracetic acid, iodobenzene diacetate, bis(trifluoroacetoxy)iodobenzene and the like in an inert solvent such as methylene chloride, chloroform, benzene, toluene and the like.
• a suitable oxidant such as peracetic acid, iodobenzene diacetate, bis(trifluoroacetoxy)iodobenzene and the like
• an inert solvent such as methylene chloride, chloroform, benzene, toluene and the like.
• the triarylbismuth(V) reagent can be used without purification or can be purified by silica gel chromatograhy.
• Triarylbismuthines may be prepared by the reaction of an appropriate aryl Grignard reagent with bismuth trichloride in an inert organic solvent such as tetrahydrofuran, diethyl ether, or 1,4-dioxane, or mixtures thereof, at or near room temperature for a period of 1 to 48 hours.
• an inert organic solvent such as tetrahydrofuran, diethyl ether, or 1,4-dioxane, or mixtures thereof.
• General procedures for the preparation and use of triaryl bismuth reagents may be found in Barton, D. H. E., et al., J. Chem. Soc. Chem. Commun., 1986, 65 and references cited therein.
• Reaction Scheme B a solution of the 3",4"-dihydroxy macrolide is treated with a triarylbismuth diacetate reagent as described in Reaction Scheme A, to give a mixture of the 3"-hydroxy-4"-O-aryl macrolide, the 3"-O-aryl-4"-hydroxy macrolide, and the 3",4"-di-O-aryl macrolide.
• 3"-hydroxy-4"-O-aryl macrolide, or 3"-O-aryl-4"-hydroxy macrolide can be treated with a different triarylbismuth diacetate reagent (prepared immediately prior to use by procedures analogous to those disclosed above), to give 3"-O-aryl-4"-O-aryl macrolides.
• the 14-hydroxy group of a macrolide may be eliminated by treatment with p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, or p-methoxybenzenesulfonic acid, or mixtures thereof, in an inert organic solvent such as benzene, or toluene or the like at a temperature of 40° C.
• the macrolide (wherein R 1 a and/or R 2 a is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl and wherein R 3 a is hydroxy or C 1-6 alkoxy, R 4 a is hydrogen, or R 3 a and R 4 a taken together form a double bond) is reduced under an atmosphere of hydrogen in the presence of a nobel metal catalyst, such as rhodium on carbon catalyst or rhodium on alumina catalyst, at a pressure of atmospheric pressure to 40 psig, at or near room temperature in an organic solvent such as ethyl acetate or ethanol for about 1 to 24 hours, or until the requisite amount of hydrogen is absorbed to reduce the olefin and give the reduced macrolide.
• a nobel metal catalyst such as rhodium on carbon catalyst or rhodium on alumina catalyst
• the C-14 hydroxy group may be elminated and the resultant double bond reduced prior to the introduction of alkenyl or alkynyl substituents at C-3" and/or C-4".
• a solution of the 4"-hydroxy 3"-methoxy macrolide in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or the like or mixtures thereof is treated with an alkyl, alkenyl or alkynyl trichloroacetimidate reagent (prepared by the reaction of an appropriate sodium alkoxide with trichloroacetonitrile, such as described by Wessel, H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans.
• an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or the like or mixtures thereof.
• an alkyl, alkenyl or alkynyl trichloroacetimidate reagent prepared by the reaction of an appropriate sodium al
• a mild acid catalyst such as trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, or p-methoxybenzenesulfonic acid, or mixtures thereof at a temperature of 20°-50° C. preferably room temperature, for a period of one hour to seven days, preferably one day, to give the 4"-O-alkyl, -alkenyl or -alkynyl 3"-methoxy macrolide.
• a mild acid catalyst such as trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bro
• ketone derivatives can be prepared by direct alkylation of the macrolide by treatment with an unsubstituted or substituted 2-bromoacetophenone in an inert solvent such as N,N-dimethylformamide or tetrahydrofuran and a fluoride source such as potassium fluoride or cesium fluoride at 25°-70° C. for a period of 24-72 hours.
• an inert solvent such as N,N-dimethylformamide or tetrahydrofuran
• a fluoride source such as potassium fluoride or cesium fluoride
• a mild acid catalyst such as trifluoromethanesulfonic acid, p-toluene-sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-nitrobenzensulfonic acid, p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, or p-methoxybenzenesulfonic acid, or mixtures thereof of at a temperature of 20°-50° C., preferably 40° C., for a period of one hour to seven days, preferably 6 hours, to give a mixture of the 3"-O-alkyl, -alkenyl or -alkynyl 4"-hydroxy macrolide, the 3"-hydroxy 4"-O-alkyl, -alkenyl or -alkynyl macrolide and the 3",4"-di-O-alkyl, -alkenyl or -
• Reaction Scheme G the procedures described in Reaction Schemes C and D may optionally be conducted following the procedures of Reaction Scheme E or F. Alternatively, the procedures described in Reaction Scheme G may be performed.
• the macrolide (wherein R 1 a and/or R 2 a is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl and wherein R 3 a is hydroxy or C 1-6 alkoxy, R 4 a is hydrogen, or R 3 a and R 4 a taken together form a double bond) is reduced with tri-n-butyltin hydride in the presence of tetrakis(triphenylphosphine)palladium(O) catalyst and acetic acid in an organic solvent such as toluene or tetrahydrofuran at or near room temperature for about 2 to 10 hours to give the reduced macrolide.
• Reaction Scheme F The procedures described in Reaction Scheme F may be conducted on the mono-substituted products of Reaction Scheme B (and visa versa) to obtain the mixed disubstituted compounds. In fact, within Reaction Schemes B and F, treatment of the mono-substituted product with a different reagent will afford the mixed disubstituted compounds.
• Protection of the C-3", C-4" and/or the C-14 hydroxy group may be accomplished by methods known in the prior art for compounds of Formula II such as by treatment with: 2,6-lutidine and triisopropylsilyl trifluoromethanesulfonate in a solution of methylene chloride; 2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate in a solution of methylene chloride; pyridine and acetic anhydride in a solution of methylene chloride; pyridine and benzoyl chloride in a solution of methylene chloride; pyridine and p-nitrobenzoyl chloride in a solution of methylene chloride; imidazole and t-butyldiphenylsilyl chloride in a solution of methylene chloride; and the like.
• the C-4", 14-dihydroxy C-3"-methoxy macrolide (or the C-3", 4", 14-trihydroxy macrolide) may be protected at C-14 as the t-butyldimethylsilyl ether by treatment with t-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride to give the C-4",3"-di-O-TBDMS macrolide (or the C-3",4", 14-tri-O-TBDMS macrolide).
• Treatment with toluenesulfonic acid in methanol results in selective removal of the C-4" silyl ether (and C-3" silyl ether, if present) to give the C-14-O-TMBDMS macrolide.
• the 4"-hydroxy-3"-R 2 O-macrolide or alternatively the 3"-hydroxy-4"-R 1 O-macrolide (not depicted) (wherein R 3 is protected hydroxy or hydrogen) may be reacted with an alkenyl trichloroacetimidate (wherein R 1 is C 3-10 alkenyl) under conditions described in Reaction Scheme F to give the C-4"-O-alkenyl macrolide.
• a variety of compounds may be prepared from the corresponding aldehyde as illustrated in Reaction Scheme J.
• the aldehyde may be reacted with a primary or secondary amine (wherein R 6 and R 7 are as defined above) in an organic solvent such as tetrahydrofuran to give an imine which is reduced in situ with a hydride reducing agent, such as potassium triphenyl borohydride or sodium cyanoborohydride, to give the macrolide bearing as amino alkoxy functionality at C-4".
• a hydride reducing agent such as potassium triphenyl borohydride or sodium cyanoborohydride
• the aldehyde may also be reduced to the corresponding alcohol by treatment with a hydride reducing agent, such as potassium triphenyl borohydride or sodium cyanoborohydride in an organic solvent such as tetrahydrofuran.
• the alcohol may be further modified by utlizing the methods of Reaction Scheme B (wherein R 1 a is unsubstituted or substituted phenyl, naphthyl or biphenyl) or Reaction Scheme F (wherein R 1 b is unsubstituted or substituted alkyl, alkenyl or alkynyl).
• Reaction Scheme J wherein R 1 a is unsubstituted or substituted phenyl, naphthyl or biphenyl
• Reaction Scheme F wherein R 1 b is unsubstituted or substituted alkyl, alkenyl or alkynyl.
• Amide derivatives may be prepared from the carboxylic acid as illustrated in Reaction Scheme K.
• the carboxylic acid may be coupled with a primary or secondary amine, HNR 6 R 7 (wherein R 6 and/or R 7 are as defined) by any of the peptide coupling methods commonly used in the art, such as with BOP reagent, DCC/HOBT, or EDC/HOBT.
• Hydroxy and keto derivatives may be prepared from the corresponding aldehyde as illustrated in Reaction Scheme L.
• the aldehyde is reacted with a nucleophilic organometallic reagent such as a Grignard reagent, an organolithium reagent, or an organocerium reagent in an organic solvent such as methylene chloride or tetrahydrofuran to give the substituted hydroxy compound.
• a nucleophilic organometallic reagent such as a Grignard reagent, an organolithium reagent, or an organocerium reagent in an organic solvent such as methylene chloride or tetrahydrofuran
• the alcohol may also be oxidized to the corresponding ketone by well known methods, such as with 4-methylmorpholine-N-oxide in the presence of tetrapropylammonium perruthenate catalyst under dehydrative conditions. Removal of hydroxy protecting groups (if necessary) gives the macrolide bearing a substituted keto alkoxy functionality at C-4".
• the procedures described in Reaction Scheme L are readily applicable to the preparation of compounds bearing analogous functionality at C-3".
• Hydroxy macrolides (wherein R 1 , R 2 , and/or R 3 bear a hydroxy group) may be further derivatized by alkylation, acylation or phosphorylation to give ether, ester or phosphate derivatives (wherein R 1 , R 2 and/or R 3 bear an --OR 11 as defined above) by procedures well known to the practitioner of the art.
• the object compounds of Formula I obtained according to the reactions as explained above can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
• the stereoisomer(s) of starting and object compounds due to asymmetric carbon atoms(s) or double bond(s) of the object compounds of Formula I may occasionally be transformed into the other stereoisomer(s), and such cases are also included within the scope of the present invention.
• compounds with asymmetric centers may occur as racemates, as diastereomeric mixtures and as individual diastereomers, with all isomeric forms of the compounds being included in the present invention.
• These may be prepared by methods such as those disclosed in publications which describe synthetic routes to fragments of the macrolide FR-900506 and the total synthesis of the macrolide FR-900506 itself (See for example, J. Am. Chem. Soc. 1989, 111, 1157; J. Am. Chem. Soc. 1990, 112, 2998; J. Org. Chem. 1990, 55, 2786; J. Am. Chem. Soc. 1990, 112, 5583. Tetrahedron Lett. 1988, 29, 277; Tetrahedron Lett.
• the compounds of the present invention are capable of forming salts with various inorganic and organic acids, and bases and such salts are also within the scope of this invention.
• acid addition salts include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate.
• Base salts (which are positive counterions defined herein as M + ) include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine and so forth.
• the basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides like benzyl bromide and others.
• the non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
• the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
• the compounds of Formula I may be employed as immunosuppressants or antimicrobial compounds by methods and in dosages known in the prior art for compounds of Formula II. These compounds possess pharmacological activity such as immunosuppressive activity, antimicrobial activity, and the like, and therefore are useful for the treatment and prevention of the resistance to transplantation or transplantation rejection of organs or tissues such as heart, kidney, liver, duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc., graft-versus-host diseases by medulla ossium transplantation, automimmune diseases such as rheumatoid arthritis, systemic lupus erthematosis, Hashimoto's thyroiditis, multiple sclerois, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases cuased by pathogenic microorganisms.
• organs or tissues such
• the compounds of Formula I are also useful for treating or preventing inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses such as: psoriasis, atopical dermatitiis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, acne, cutaneous eosinophilias or Alopecia areata.
• immunologically-mediated illnesses such as: psoriasis, atopical dermatitiis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angio
• the compounds of Formula I are useful in hair revitalizing, such as in the treatment or prevention of male pattern alopecia or alopecia senilis, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth.
• the compounds of Formula I are further useful for treating or preventing reversible obstructure airways disease, including conditions such as asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hper-responsiveness), bronchitis and the like.
• the compounds of Formula I may also be useful for treating hepatic injury associated with ischemia.
• the compounds of Formula I are also useful for treating multidrug resistance of tumor cells, (i.e. enhancing the activity and/or sensitivity of chmmoterapeutic agents), preventing or treating inflammation of mucosa or blood vessels, LTB 4 -mediated diseases, gastric ulcers, vascular damage cuased by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) necrotizing enterocolitis, or intestinal lesions associated with thermal burns, cytomegalovirus infection, particularly HCMV infection, idiopathic thrombocytopenic purpura and Basedow's disease.
• multidrug resistance of tumor cells i.e. enhancing the activity and/or sensitivity of chmmoterapeutic agents
• preventing or treating inflammation of mucosa or blood vessels i.e. enhancing the activity and/or sensitivity of chmmoterapeutic agents
• inflammation of mucosa or blood vessels i.e
• the compounds of Formula I are also useful for treating or preventing renal diseases selected from interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases selected from multiple myositis, Guillain-Barre syndrom, Meniere's disease and radiculopathy; enocrine diseases selected from hyperthyroidism; hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases such as ostoporosis; respiraoty diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; eye diseases selected from herpetic keratitis, conical cornea, dystronphia epithelialis cornease, corneal leukmas, ocular pemphigus, Mooren's ulcer, scleritis and Grave's ophthalmopathy
• compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
• the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
• the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
• the compounds of Formula I may be utilized with hydroxypropyl methylcellulose essentially as described in U.S. Pat. No. 4,916,138, issued Apr. 10, 1990, or with a surfactant essentially as described in EPO Publication 0,428,169.
• Oral dosage forms may be prepared essentially as described by T.
• Dosage forms for external application may be prepared essentially as described in EPO Publication 0,423,714.
• the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
• a compound of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections intravenous, intramuscular, intrasternal injection or infusion techniques.
• Dosage levels of the compounds of the present invention are of the order from about 0.005 mg to about 50 mg per kilogram of body weight per day, preferably from about 0.1 mg to about 10 mg per kilogram of body weight per day, are useful in the treatment of the above-indicated conditions (from about 0.7 mg to about 3.5 per patient per day, assuming a 70 kg patient).
• the compounds of the present invention may be administered on an intermittent basis; i.e. at daily, semiweekly, weekly, semi-monthly or monthly intervals.
• the amount of active ingredient that may be combined with the carrier materials to produce a signle dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• Dosage unit forms will generally contain from about 0.5 mg to about 500 mg of active ingredient, and preferably about 0.5 mg to about 100 mg of active ingredient.
• the compound of Formula I may be formulated within the range of, for example, 0.0001% to 60% by weight, preferably from 0.001 to 10% by weight, and most preferably from about 0.0005 to 0.8% by weight.
• the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
• triphenyl bismuth diacetate prepared immediately prior to use by addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenyl bismuth carbonate (127 mg, 0.253 mmol. 2 eq) in CH 2 Cl 2 (1 ml)].
• the reaction vessel was capped and the mixture stirred for five days.
• the reaction mixture was diluted with several milliliters of saturated aqueous NaHCO 3 and extracted 4 times with CH 2 Cl 2 .
• reaction vessel was capped and the mixture stirred for two days.
• the reaction mixture was diluted with several milliliters of saturated aqueous NaHCO 3 and extracted 2 times with CH 2 Cl 2 .
• the organic extracts were combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
• reaction flask was then fitted with a reflux condenser and the mixture warmed to 40° C. After 20 hours the reaction mixture was cooled, diluted with saturated aqueous NaHCO 3 (10 mL) and extracted 4 times with CH 2 Cl 2 . The organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
• reaction vessel was capped and the mixture stirred for 20 hours at which time TLC analysis showed the reaction to be incomplete.
• the mixture was treated with additional tri(4-tolyl) bismuth diacetate (0.234 mmol) and stirred for 24 hours then poured into saturated aqueous NaHCO 3 and extracted 2 times with CH 2 Cl 2 . The organic extracts were combined, drried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
• reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. for 5 hours then stirred without heating. After 18 hours the reaction mixture was diluted with saturated aqueous NaHCO 3 and extracted 2 times with CH 2 Cl 2 . The organic extracts were combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
• the reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. After 4 hours the mixture was cooled, diluted with saturated aqueous NaHCO 3 , and extracted 2 times with CH 2 Cl 2 . The extracts were combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
• reaction flask was then fitted with a reflux condenser and the mixture was warmed to 40° C. for 4 hours. After stirring an additional 16 hours at room temperature TLC analysis showed the reaction to be incomplete.
• the reaction mixture was further treated with tri(1-naphthyl)bismuth diacetate (0.15 mmol) and heated to 40° C. for 4 hours.
• the mixture was cooled, diluted with saturated aqueous NaHCO 3 , and extracted 2 times with CH 2 Cl 2 . The extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• the reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. for 5 hours then stirred at room temperature. After 16 hours the mixture was diluted with saturated aqueous NaHCO 3 extracted 2 times with CH 2 Cl 2 . The extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• the reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. After 4 hours the heating was discontinued and the mixture stirred at room temperature for 16 hours. The mixture was then diluted with saturated aqueous NaHCO 3 and extracted 2 times with CH 2 Cl 2 . The extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. for 4 hours then stirred at room temperature. After 3 days the reaction mixture was diluted with saturated aqueous NaHCO 3 and extracted 3 times with CH 2 Cl 2 . The extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. After 6 hours the mixture was allowed to cool to room temperature and stirred an additional 16 hours.
• the reaction mixture was diluted with saturated aqueous NaHCO 3 and extracted 2 times with CH 2 Cl 2 . The extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• the mixture was stirred for 96 hours.
• the reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted 4 ⁇ with CH 2 Cl 2 .
• the organic extracts were combined and dried over anhydrous Na 2 SO 4 .
• the mixture was filtered and concentrated in vacuo.
• the reaction mixture was cooled and diluted with CH 2 Cl 2 .
• the reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted 4 ⁇ with CH 2 Cl 2 .
• the organic extracts were combined and dried over anhydrous Na 2 SO 4 .
• the mixture was filtered and concentrated in vacuo.
• reaction was quenched with saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4 ⁇ with methylene chloride.
• organic extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concnetrated in vacuo.
• the products were separated by preparative TLC on silica gel (2:1 hexanes/acetone).
• reaction was quenched with saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4 ⁇ with methylene chloride. The organic extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The products were separated by preparative TLC on silica gel (2:1 hexanes/acetone).
• reaction mixture was stirred 12 h.
• the reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted 4 ⁇ with CH 2 Cl 2 .
• the organic extracts were combined and dried over anhydrous Na 2 SO 4 .
• the mixture was filtered and concentrated in vacuo.
• reaction mixture was quenched by addition of saturated aqueous NaHCO 3 and extracted 2 ⁇ with CH 2 Cl 2 .
• the organic extracts were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
• Trifluoromethanesulfonic acid (4.5 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 18 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (156 mg).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 16 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (17 mg).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg 3"-ether).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 5 ml). The combined organic were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg 3"-ether).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 8 ml). The combined organic were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 3"-ether).
• Trifluoromethanesulfonic acid (2 ⁇ l neat) wad added slowly via syringe and the mixture stirred at room temperature. After 35 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 ⁇ 8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparation TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg 3"-ether).

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• 1992
  • 1992-05-01 US US07/875,036 patent/US5250678A/en not_active Expired - Fee Related
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